Heparinase III and methods of specifically cleaving therewith
||Heparinase III and methods of specifically cleaving therewith
||Liu, et al.
||November 25, 2008
||July 22, 2005
||Liu; Dongfang (Yorktown Heights, NY)
Pojasek; Kevin (Cambridge, MA)
Shriver; Zachary (Boston, MA)
Holley; Kristine (Boston, MA)
El-Shabrawi; Yosuf (Graz, AT)
Venkataraman; Ganesh (Bedford, MA)
Sasisekharan; Ram (Bedford, MA)
||Massachusetts Institute of Technology, Inc. (Cambridge, MA)|
|Attorney Or Agent:
||Wolf Greenfield & Sacks, P.C.
|Field Of Search:
|U.S Patent Documents:
|Foreign Patent Documents:
||0 140 781; 0 114 589; 0 244 236; 0 394 971; 0 433 225; 0 342 215; 0 557 887; WO 92/01003; WO 93/05167; WO 93/08289; WO 93/10450; WO 93/15406; WO 93/19096; WO 93/19734; WO 94/12618; WO 94/21689; WO 95/13830; WO 95/34635; WO 96/01648; WO 97/06783; WO 97/11684; WO 97/16556; WO 98/04902; WO 00/12726; WO 00/65521; WO 06/105313; WO 06/105315; WO 07/044471
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||The invention relates to heparinase III and mutants thereof. Modified forms of heparinase III having reduced enzymatic activity which are useful for a variety of purposes, including sequencing of heparin-like glycosaminoglycans (HLGAGs), removing active heparan sulfate from a solution, inhibition of angiogenesis , etc. have been discovered according to the invention. The invention in other aspects relates to methods of treating cancer and inhibiting tumor cell growth and/or metastasis using heparinase III, or products produced by enzymatic cleavage by heparinase III of HLGAGs.
1. A method of cleaving comprising: contacting a linear polysaccharide with a disaccharide repeat unit of a uronic acid [.alpha.-L-iduronic acid (I) or .beta.-D-glucuronic acid (G)]linked 1, 4 to .alpha.-D-hexosamine (H) with a protein comprising a modified heparinase III in vitro, wherein the modified heparinase III has the amino acid sequence of the mature peptide of SEQ ID NO: 2, wherein at least one histidine residue selectedfrom the group consisting of His36, His105, His110, His139, His152, His225, His234, His241, His424, His469, and His539 has been substituted with a residue selected from the group consisting of alanine, serine, tyrosine, threonine, and lysine.
2. The method of claim 1, wherein the modified heparinase III has at least one substitution at a histidine residue selected from the group consisting of His110, His225 and His241.
3. The method of claim 1, wherein the modified heparinase III has a substitution at His110.
4. The method of claim 1, wherein the modified heparinase III has a substitution at His241.
5. The method of claim 1, wherein the modified heparinase III has a substitution at His225.
6. The method of claim 5, wherein the His225 is substituted with alanine.
7. The method of claim 1, wherein the modified heparinase III is in a composition that comprises a pharmaceutically acceptable carrier.
8. The method of claim 1, wherein the modified heparinase III is immobilized on a solid support.
9. The method of claim 8, wherein the solid support is a sheet, test strip, membrane, bead, test tube, microplate well or the external surface of a rod.